Trabectedin
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Trabectedin
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| Systematic (IUPAC) name | |
| (1'R,6R,6aR,7R,13S,14S,16R)-6',8,14-trihydroxy- 7',9-dimethoxy-4,10,23-trimethyl-19-oxo-3',4',6,7, 12,13,14,16-octahydrospiro[6,16-(epithiopropano oxymethano)-7,13-imino-6aH-1,3-dioxolo[7,8]isoquino [3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-5-yl acetate |
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| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| Chemical data | |
| Formula | C39H43N3O11S |
| Mol. mass | 761.84 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Not applicable (IV only) |
| Protein binding | 94 to 98% |
| Metabolism | Hepatic (mostly CYP3A4-mediated) |
| Half life | 180 hours (mean) |
| Excretion | Mostly fecal |
| Therapeutic considerations | |
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| Legal status | |
| Routes | Intravenous |
Trabectedin (also known as ecteinascidin 743 or E-743) is an anti-tumor drug. It was developed by Zeltia and Johnson & Johnson Pharmaceutical Research and Development and is sold under the brand name Yondelis. It is approved for use in Europe and South Korea for the treatment of advanced soft tissue sarcoma.[1] It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas.[2] The European Commission and the US Food & Drug Administration have granted orphan drug status to trabectedin for soft tissue sarcomas and ovarian cancer.
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[edit] History
First isolated from aqueous ethanol extract of tunicates in 1969, the complex molecule was found to have impressive cytotoxic activities in the pico- to nanomolar range. It is composed of 3 tetrahydroquinoline moieties, 8 rings including one 10-membered heteocyclic ring containing a cystine residue, and 7 chiral centers. This structure was not determined until 1984, and was first prepared synthetically by Elias James Corey in 1996.[3]
[edit] Synthesis
The biosynthesis of trabectidin is believed to involve the dimerization of two tyrosine residues to form the pentacyclic core of the molecule. The total synthesis by E.J. Corey used this proposed biosynthesis to guide their synthetic strategy. The synthesis uses such reactions as the Mannich reaction, Pictet-Spengler reaction, the Curtius rearrangement, and chiral rhodium-based diphosphine catalyzed enantioselective hydrogenation. A separate synthetic process also involved the Ugi reaction to assist in the formation of the pentacyclic core. This reaction was unprecedented for using such a one pot multi-component reaction in the synthesis of such a complex molecule.
[edit] Mechanism of action
The biological mechanism of action is believed to involve the production of superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis. The actual mechanism is not yet known, but is believed to proceed from reduction of molecular oxygen into superoxide via an unusual auto-redox reaction on a hydroxyquinone moiety of the compound following. There is also some speculation the compound becomes 'activated' into its reactive oxazolidine form.
[edit] References
- ^ S.Korea approves Zeltia cancer drug Yondelis, Reuters.com, May 8, 2008
- ^ Yondelis at PharmaMar.com
- ^ E. J. Corey, David Y. Gin, and Robert S. Kania (1996). "Enantioselective Total Synthesis of Ecteinascidin 743". J. Am. Chem. Soc. 118 (38): 9202-9203.
